Chemotherapeutic compositions

ABSTRACT

The present invention relates to the treatment of gastrointestinal disease and/or cancer, and a method of weight gain, via the ingestion of polymeric compositions in humans, animals or birds in need of said treatment. The invention provides methods for the treatment of cancer, the treatment and/or prevention of gastrointestinal disease and/or infection and/or diarrhoea, and a method for increasing weight gain in humans, animals or birds comprising administering to said humans, animals or birds an effective amount of a pharmaceutical or veterinary composition, or feed additive, comprising an effective amount of a polymer and/or copolymer, having the repeating polymeric unit (I),  
                 
 
     wherein R is H or alkyl, usually C 1  to C 4 , or this unit in hydrated, hemiacetal or acetal form, together with a pharmaceutically or veterinarally acceptable carrier, diluent, adjuvant, excipient and/or controlled release system.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a Rule 53(b) divisional of U.S.application Ser. No. 08/952,648 which is the national phase of PCTInternational Application No. PCT/AU96/00328 filed May 30, 1996, whichclaims priority on Australian Application No. PN 3276 filed May 30,1995. The entire contents of PCT Application No. PCT/AU96/00328 ishereby incorporated by reference.

TECHNICAL FIELD

[0002] The present invention relates to the treatment ofgastrointestinal disease, and/or cancer, and a method of weight gain,via the ingestion of polymeric compositions in humans, animals or birdsin need of said treatment.

BACKGROUND ART

[0003] Under the conditions of intensive pig-rearing, post weaningcolibacillosis is ubiquitous. For example, intensive pig-rearing is usedthroughout Europe, the United States and Australia. For example, in theUnited States, post-weaning colibacillosis is the most common cause ofmortality in the weaner pig (Leman et al., 1986). The disease isassociated with the proliferation of Escherichia coli bacteria in theanterior small intestine after weaning, and gives rise to either death,or the young weaner failing to make normal weight-gains. Othermicrobiological diseases are common and often accompany colibacillosisin pigs as well as in other animals in intensive rearing conditions,especially poultry.

[0004] In the past, attempts have been made to control disease by theingestion of antimicrobial compositions or by vaccination, neither ofwhich has proved entirely effective.

[0005] The rationale behind the lack of success surrounding ingestion ofantimicrobial compositions has been the fact that proteinaceousfeedstuffs and the contents of the gastrointestinal tract present areactive and hazardous environment to any chemotherapeutic agent andhence, in vitro active antimicrobial agent will often not be effectivewhen used in vivo within the gastrointestinal tract.

[0006] Further, to be antimicrobially effective in a practical way,there is often the restrictive demand that the gastrointestinal diseasecontrolling agent should reasonably maintain the very lowmicrobiological content in the duodenum, yet the very high content inthe lower parts of the intestine.

[0007] As well, it does not follow that even in vivo effectiveantimicrobials will give weight-gains, since it is common that even acocktail of several such commercially used antimicrobials only givesrise to variable, partial or even negative relative weight-gains overcontrol animals.

[0008] Accordingly, there is a need for improvements in the preventionand/or treatment of disease via ingestion of antimicrobial compositionsin humans and/or animals and/or birds in need of said treatment.Furthermore, there is the need for the attainment of weight gains ofsaid humans and/or animals and/or birds undergoing said treatment.

[0009] The present invention provides polymers and/or copolymerspreferably derived from acrolein and having the polymeric repeatingunit:

[0010] wherein R is H or alkyl, usually C₁ to C₄ or this unit inhydrated, hemiacetal or acetal form and illustrated non-comprehensivelyof all possible structures, by the following formulae:

[0011] wherein n is one or more and R is as defined above; hereinafterreferred to as the “Subject Polymers”, as broad spectrum in vivoantimicrobials and/or anti-cancer agents suitable for treatment by theoral route.

[0012] It is known that the rate of passage of molecules acrossmembranes has an inverse relationship to their molecular weights. Thus,it is widely and generally accepted in the art that molecules taken bythe oral route and having molecular weight <1000, will have theirpassage across the gut so restricted, and consequently any potentialtoxicity will be effectively minimized.

[0013] The Subject Polymers, being aldehydic, are especially reactivewith protein. (In fact, in microbiological assays, the routine andfacile method of quenching/destroying the activity of the SubjectPolymers is to add protein.) Hence, the Subject Polymers would not beexpected to exhibit significant microbiological activity in theintestine, especially in the presence of proteinaceous feed.

[0014] Therefore, the present invention provides a method of preventionand/or treatment of gastrointestinal disease in humans, animals or birdsresulting from the microbial infection of the gastrointestinal tract,and a method for increasing weight gain in humans, animals or birdshaving gastrointestinal disease and/or infection, comprisingadministering an effective amount to said humans, animals or birds of apharmaceutical composition or feed additive, comprising an effectiveamount of the Subject Polymers together with a pharmaceutically orveterinarally acceptable carrier, diluent, adjuvant, excipient orcontrolled release system.

OBJECT OF THE INVENTION

[0015] It is an object of the present invention to provide methods forthe prevention and treatment of dysfunctional/pathological states in ahuman, animal or bird, especially, those states within thegastrointestinal tract associated with colibacillosis, diarrhea,mortality and/or reduced weight gains.

DISCLOSURE OF THE INVENTION

[0016] The present invention is based upon a series of discoveriesherein:

[0017] First, it has now been discovered that the Subject Polymers,being of high molecular weight are inhibited in passage throughbiological membranes, and have facilitated applications in thegastrointestinal tract, since passage through the gut and into thebloodstream to potentially cause toxicity is minimized. In particular,it has been discovered that the Subject Polymers have molecularweights >1000, and generally have molecular weights >2000, whicheffectively minimize their passage across the intestinal membranes andas a result, it has been found herein that whilst the Subject Polymersexhibit toxicity following intra-venous injection, they exhibit notoxicity when administered orally. Hence it has been discovered that theSubject Polymers have minimized toxicities and that they have associatedadvantages when used for chemotherapeutic purposes, in any specieshaving gut membranes, for example, humans, animals or birds.

[0018] Generally, the Subject Polymers formed by ionicinitiation/catalysis are more hydrophilic than those formed by freeradical initiation/catalysis, and hydrophilicity of the Subject Polymersmay generally be increased by inclusion within them of hydrophilicgroups, especially carboxyl groups, or of hydrophilic monomers,especially acrylic acid. Particularly, carefully heating the SubjectPolymers formed by ionic initiation/catalysis with ample air from roomtemperature to up to 100° C., and preferably up to between 80-85° C.,produces the Subject Polymers having 0.1-5 moles of carboxyl groups/kg,aqueous soluble at the pH of the duodenum especially, and preferred forthe applications in gastrointestinal tracts described and envisagedherein.

[0019] The Subject Polymers have the following properties:

[0020] The Subject Polymers have an unusually broad in vivoantimicrobial profile, providing a method of treatment ofgastrointestinal disease in humans, animal or birds.

[0021] It has been shown that the Subject Polymers provide increasedweight gains in humans, animals or birds.

[0022] It has also been shown that the Subject Polymers are in vivoanti-cancer agents.

[0023] According to a first embodiment of the invention there isprovided a method of in vivo cancer treatment in humans, animals orbirds comprising administering to said humans, animals or birds aneffective amount of a pharmaceutical or veterinary composition or feedadditive, comprising an effective amount of polymers and/or copolymershaving the repeating polymeric unit:

[0024] wherein R is H or alkyl, usually C₁ to C₄, or this unit inhydrated, hemiacetal or acetal form and illustrated non-comprehensivelyof all possible structures, by the following formulae:

[0025] wherein n is one or more and R is as defined above; together witha pharmaceutically or veterinarally acceptable carrier, diluent,adjuvant, excipient and/or controlled release system.

[0026] According to a second embodiment of the invention there isprovided a method for the treatment and/or prevention ofgastrointestinal disease and/or infection and/or diarrhea in humans,animals or birds resulting from a microbial infection of thegastrointestinal tract in said humans, animals or birds, comprisingadministering to said humans, animals or birds an effective amount of apharmaceutical or veterinary composition or feed additive, comprising aneffective amount of a polymer and/or copolymer as defined in the firstembodiment of the invention, together with a pharmaceutically orveterinarally acceptable carrier, diluent, adjuvant, excipient and/orcontrolled release system.

[0027] According to a third embodiment of the invention there isprovided a method of increasing weight gain in humans, animals or birdshaving cancer and/or gastrointestinal microbial disease and/orinfection, in said humans, animals or birds, comprising administering tosaid humans, animals or birds an effective amount of a pharmaceutical orveterinary composition or feed additive, comprising an effective amountof a polymer and/or copolymer as defined in the first embodiment of theinvention, together with a pharmaceutically or veterinarally acceptablecarrier, diluent, adjuvant, excipient and/or controlled release system.

[0028] In terms of the Subject Polymers being a prevention and/ortreatment for gastrointestinal disease, it has now been shown thatfarm-piglets given the Subject Polymers ad libitum in their drinkingwater, have reduced numbers of diarrhea days and lower counts of E. coliin their excreta. Moreover, the effect as proposed, is markedly greaterthan the partial effect exhibited by the administration of commercialantimicrobial agents together with vaccination.

[0029] In addition, it has now been discovered that the Subject Polymersin a polymeric controlled-release system as well as leading to fewerdiarrhea days in the animal, also gave rise to extraordinarily highweight-gains. As exemplified in Example 17, piglets displayed lowermortality, and weight gains of some 46% above control piglets.

[0030] Therefore, it is proposed that the Subject Polymers should beprovided as an additive to the animal's solid feed, in the form of apolymeric controlled-release system, since then, the Subject Polymerswould be released slowly and mainly in the duodenum. Further, it is nowproposed that having the Subject Polymers in a controlled-release systemwill reduce any destructive chemical reaction between the SubjectPolymers and either constituents of the gastro-intestinal tract or theproteinaceous feed, especially during the essential pre-heatsterilization of the feed. Furthermore, any rejection by the animal dueto taste, will be reduced.

[0031] When using the Subject Polymers for the treatment of diseaseand/or infection in humans, animals or birds in need of treatment, forexample in piglets having diarrhea associated with colibacillosis, it ispreferred to begin dosing immediately after weaning and to alwayscontinue for the next 5 days, sometimes for the next 30 days, butpreferably at least for the next 15 days after weaning; at any time thatsuch symptoms of diarrhea are observed. Treatment in acontrolled-release form is preferred and containing theoretically 5%-50%w/w Subject Polymers but preferably, 20%-30% w/w. Preferably thecontrolled-release form/pellet is added to the feed, either duringproduction of the feed or during feeding such that the feed contains1%-20% w/w and preferably 2%-8% w/w of pellet. If for example a pigletof 5 kg daily eats 500 g of feed with 4% w/w controlled-release pelletcontaining 25% w/w Subject Polymers—this calculates to a dose rate ofSubject Polymers of 1000 mg/kg(liveweight)/day; in a controlled-releaseform a dose rate of 50-5000 mg/kg/day is practical but 500-2500mg/kg/day is preferred. Smaller dose rates of 25-500 mg/kg/day should beused when the Subject Polymers are given in a non-controlled-releaseform. Dose protocols and rates are similar for other microbiologicalinfections and for cancer.

[0032] Both the in vivo antimicrobial activity in the presence ofrelatively huge quantities of reactive proteins in the gastro-intestinaltract, and the range of chemotherapeutic activities of the SubjectPolymers, revealed herein, are surprising. Also, in unpublished work,the Subject Polymers have been found to exhibit significantanti-coagulant activities in human or a range of various animal bloods.This particular range of surprising in vivo activities suggests thatunexpectedly, the Subject Polymers have such activities related tolectin-selectin-integrin type adsorptive inter-actions.

[0033] Compositions for administration in the method of the inventionmay be prepared by means known in the art for the preparation ofcompositions (such as in the art of veterinary and pharmaceuticalcompositions) including blending, grinding, homogenizing, suspending,dissolving, emulsifying, dispersing and where appropriate, mixing of theSubject Polymers together with selected excipients, diluents, carriersand adjuvants.

[0034] For oral administration, the pharmaceutical or veterinarycomposition may be in the form of tablets, lozenges, pills, troches,capsules, elixirs, powders, including lyophilized powders, solutions,granules, suspensions, emulsions, syrups and tinctures. Slow-release, ordelayed-release, forms may also be prepared, for example in the form ofcoated particles, multi-layer tablets or microgranules.

[0035] It is preferred that the controlled release system comprises apH-sensitive, crosslinked, water-absorbent pellet, which when wet is agel.

[0036] Solid forms for oral administration may contain pharmaceuticallyor veterinarally acceptable binders, sweeteners, disintegrating agents,diluents, flavorings, coating agents, preservatives, lubricants and/ortime delay agents. Suitable binders include gum acacia, gelatin, cornstarch, gum tragacanth, sodium alginate, carboxymethylcellulose orpolyethylene glycol. Suitable sweeteners include sucrose, lactose,glucose, aspartame or saccharine. Suitable disintegrating agents includecorn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum,bentonite, alginic acid or agar. Suitable diluents include lactose,sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate,calcium silicate or dicalcium phosphate. Suitable flavoring agentsinclude peppermint oil, oil of wintergreen, cherry, orange or raspberryflavoring. Suitable coating agents include polymers or copolymers ofacrylic acid and/or methacrylic acid and/or their esters, and/or theiramides, waxes, fatty alcohols, zein, shellac or gluten. Suitablepreservatives include sodium benzoate, vitamin E, alpha-tocopherol,ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.Suitable lubricants include magnesium stearate, stearic acid, sodiumoleate, sodium chloride or talc. Suitable time delay agents includeglyceryl monostearate or glyceryl distearate.

[0037] Liquid forms for oral administration may contain, in addition tothe above agents, a liquid carrier. Suitable liquid carriers includewater, oils such as olive oil, peanut oil, sesame oil, sunflower oil,safflower oil, arachis oil, coconut oil, liquid paraffin, ethyleneglycol, propylene glycol, polyethylene glycol, ethanol, propanol,isopropanol, glycerol, fatty alcohols, triglycerides or mixturesthereof.

[0038] Suspensions for oral administration may further comprisedispersing agents and/or suspending agents. Suitable suspending agentsinclude sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethyl-cellulose, polyvinyl-pyrrolidone, sodium alginate orcetyl alcohol. Suitable dispersing agents include lecithin,polyoxyethylene esters of fatty acids such as stearic acid,polyoxyethylene sorbitol mono-or di-oleate, -stearate or -laurate,polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate andthe like.

[0039] The emulsions for oral administration may further comprise one ormore emulsifying agents. Suitable emulsifying agents include dispersingagents as exemplified above or natural gums such as gum acacia or gumtragacanth.

[0040] According to a fourth embodiment of the invention there isprovided a method of producing pellets, the pellets comprising polymersand/or copolymers as defined in the first embodiment of the invention,together with a pharmaceutically or veterinarally acceptable carrier,diluent, adjuvant, excipient and/or controlled release system, mainlywithin a polymeric matrix. The method comprising adding a polymericmatrix to a solution, suspension or emulsion of the polymers and/orcopolymers as defined in the first embodiment of the invention.

[0041] According to a fifth embodiment of the invention there isprovided a method of producing pellets or like solid composition, thepellets comprising polymers and/or copolymers as defined in the firstembodiment of the invention, mainly within a polymeric matrix, saidmethod as defined in the fourth embodiment of the invention andcomprising the steps of:

[0042] (i) dissolving said polymers and/or copolymers in an aqueousalkaline or basic solution;

[0043] (ii) neutralizing said solution with acid;

[0044] (iii) adding to said neutralized solution insoluble,cross-linked, absorbent polymers of acrylic acid and/or copolymers ofacrylamide and acrylic acid, to form wet, swollen pellets; and

[0045] (iv) optionally, wholly or partially drying said wet swollenpellets.

[0046] The so-formed wet, swollen pellets may be used either wet,partially dried or wholly dried, as an additive to, for example, animalfeed. This system is further designed so that the carboxyl-containinggroups of the outer polymeric matrix cause the Subject Polymers toremain essentially contained within the matrix when in the acidicenvironment of the stomach. However, in the alkaline environment of theduodenum, the carboxyl groups of the matrix become ionized andmutually-repelling, and the pellet rapidly swells to allow the SubjectPolymers, aided by repulsion among their own ionic groups, to beexcluded by a diffusion process, approximately matching the speed ofpassage of feed through the duodenum.

[0047] In this invention, the term, “controlled release system” is usedin the same context as that in, and includes the same range of examplesas quoted in “Controlled Drug Delivery” (Robinson & Lee, 1987). Manyother pH-sensitive controlled-release systems which are known in the art(Robinson and Lee, 1987) may be substituted for the polymer of acrylicacid or copolymer of acrylamide and acrylic acid. For example, solubleand anionic or insoluble, cross-linked and anionic, cellulosic systemsor soluble and anionic, or insoluble, cross-linked and anionic polymersderived from any generic acrylic acid and/or its derivatives. Suchcross-linked and insoluble polymers are preferred since they swell andalso, are less likely to be metabolized.

[0048] In summary, the compositions described herein may be used tocontrol cancer and/or microbiological disease and especially result ingreater weights of humans, animals or birds having gastrointestinalinfections. The invention is applicable in humans, animals or birdshaving microbiological diseases of the gastrointestinal tract forexample, Escherichia coli. A preferred use is to bring about greaterweights in newly-weaned piglets having diarrhea and associated with theproliferation of Escherichia coli bacteria in the anterior smallintestine. The invention may be applicable in humans havinggastrointestinal disease, for example, from Staphylococcus aureus and/orHelicobactor pylori bacteria.

[0049] The invention will now be described with reference to specificExamples, which should not be construed as limiting on the scopethereof.

EXAMPLES 1 TO 13 Preparations and Structures of Subject Polymers Example1

[0050] (a) Using a free radical initiator/free radical catalyst: 9.64 gdistilled acrolein and 25 g methanol were placed in a 100 ml roundbottom flask and purged with nitrogen. 0.525 g benzoyl peroxide wasadded and the solution stirred under nitrogen at 60° C. The reaction wasallowed to continue for a total of ca. 88 hours. After this time thereaction solution had become strongly yellow in color and had a solidscontent of 30.5%. ¹³C-NMR (300 MHZ) δ(relative to d₄-methanol at 49.00):33.27 (CH); 33.53 (CH); 33.79 (CH); 33.87 (CH₂); 37.03 (CH); 37.29 (CH);37.54 (CH); 37.64 (CH₂); 97.15 (CH); 103.37 (CH); 104.34 (CH); 139.36(CH); 139.78(CH₂); 196.72 (CH). The ¹³C-NMR spectrum shows some residualacrolein with the aldehyde carbon at δ196.72 and the vinylic CH₂ and CHat δ139.78 and δ139.36, respectively; apart from the δ196.72 (CH)resonance absorption, there was no other attributed to —CHO. Thespectrum is consistent with polymeric acrolein consisting of fusedtetrahydropyran rings and some free dihydroxy methyl groups. The ringsexist in either the boat or chair conformations giving rise to morechemical shifts than may be expected.

[0051] Typically, as an indication of molecular weight, the polyacroleinwas found to have a retention time which was shorter than that ofpolyethyleneglycol 2,000 on a Porasil GPC 60 Angstrom column using aWaters Associated Model ALC/GPC 204 liquid chromatograph fitted with adifferential refractometer R401.

[0052] (b) Using an ionic initiator/catalyst: 1.6 g distilled acroleinwas made up to 20 ml with demonized water in a 200 ml beaker and then,ca. 0.5 ml of 0.2M sodium hydroxide added with stirring to pH ca. 10-11.The solution became cloudy and a white precipitate began to form. Thecontents were stirred for a further 2 hours and then filtered. Theprecipitate was washed thoroughly with demonized water until thefiltrate was neutral. The product may be carefully heat-dried in contactwith ample air, initially at ambient temperatures and then attemperatures up to about 100° C. Alternatively, as in this case, theproduct may be dried under vacuum to a white-pale yellow, fine powder;dissolved in methanol, and it may be evaporated down to dryness and thenagain, dissolved in methanol or other solvents. Often, the SubjectPolymers have 0.1-5 moles of carboxyl groups/kg and were found to haveGPC retention times which were mainly shorter than that of polyethyleneglycol 2,000. ¹³C-NMR (300 MHz) δ(relative to d₄-methanol at 49.00):19-31 (CH₂); 35.95 (CH₂); 37-42 (CH); 62-73 (CH₂); 73-81 (CH); 92-95(CH); 96-103 (CH); 114-120 (CH₂); 134-141 (CH); 196.0 (CH).

[0053] In experiments using in each case, 2 groups of 10 Swiss whitemice (treated and control, respectively) it was found that solutions ofthe Subject Polymers in aqueous triethanolamine adjusted to pH 8, had anacute intra-venous toxicity of 320 mg/kg, and acute oral toxicityof >5000 mg/kg (no deaths nor abnormal signs were apparent over 14days).

Example 2

[0054] 6.489 g distilled acrylic acid, 0.56 g distilled acrolein and 15g methanol were placed in a 50 ml round bottom flask and purged withnitrogen. 0.33 g benzoyl peroxide was added and the solution stirredunder nitrogen at 60-65° C. The reaction was continued for ca. 66 hours.After this time the contents of the flask had become very viscous,having a solids content of 57.7% (indicating 100% conversion).

[0055] A sample of the viscous material was placed on a petri dish anddried on a hot plate to remove solvent. Drying was completed in an ovenat 80° C. and a transparent, slightly yellow colored polymer wasobtained. The copolymer is completely soluble in warm water (ca. 50° C.)and once dissolved remains so, even on cooling the solution.

[0056] In order to ensure that the solids obtained were polymeric, asimple dialysis experiment was performed: 10 g of an aqueous solutioncontaining 0.65% solids was placed in a dialysis tube. This wasirrigated with water continuously for ca. 66 hours. The solution in thedialysis tube was then recovered and the solids content determined at0.68%. Since the solids were completely retained and the lower limit forsolids penetration through the dialysis tube is 2000 mwt, it isconcluded that the solids are polymeric.

Example 3

[0057] 2.8 g of acrolein diethyl acetal was placed in a 100 ml roundbottom flask and the contents purged with nitrogen. A solution of 0.216g potassium persulphate in 7.5 g water was added with stirring, undernitrogen. The flask was placed in an oil bath at 60-70° C. and stirredfor ca. 20 hours. A yellow solid was recovered and dried at 50° C.;weight 0.915 g.

Example 4

[0058] 4 g distilled acrylic acid, 4.81 g acrolein diethyl acetal and 15g methanol were placed in a 50 ml round bottom flask and purged withnitrogen. Then 0.3 g benzoyl peroxide was added and stirring continuedunder nitrogen at 60-65° C. for 70 hours (solids determination indicateda 50% conversion). ¹³C-NMR (300 MHz) δ(relative to d₄-ethanol at 49.00):15.58 (CH₃); 18.31 (CH₃); 35.52 (CH₂); 36.24 (CH₂); 37.07 (CH₂); 42.36(CH); 42.85 (CH); 58.32 (CH₂); 130.00 (CH); 131.57 (CH₂); 178.51 (CH).

Example 5

[0059] 3.8 g of acrolein diethyl acetal, 3.3 g vinyl pyrrolidone and 10g methanol were placed in 50 ml round bottom flask and thoroughly purgedwith nitrogen. 0.71 g azobisisobutyronitrile was added and the flaskheated in an oil bath at 60-65° C., with stirring under nitrogen for 72hours when the conversion was 44%. The copolymer was found to be solublein methanol.

Example 6

[0060] In a similar technique to the above, 3.9 g acrolein diethylacetal, 1.16 g acrylic acid, 7.5 ml water and 0.216 g potassiumpersulphate were heated under nitrogen, with stirring in an oil bath at60-70° C. for ca. 24 hours when a white waxy material was recovered; itwas insoluble in water, but swelled in methanol, acetone,tetra-hydrofaran or methyl ethyl ketone.

Example 7

[0061] A similar result was achieved through heating and stirring in theusual way to the above: 14.5 g methanol, 3.62 g distilled acrolein, 1.21g distilled acrylic acid and 0.265 g benzoyl peroxide. After 40 hoursthe conversion was 40%.

Examples 8-11

[0062] A 50:50 mixture of monomers was treated as follows: 2.35 gdistilled acrolein, 2.88 g distilled acrylic acid and 14.5 g methanolwere placed in a 50 ml round bottom flask and flushed with nitrogen.0.2625 g benzoyl peroxide was added and after heating at 60-70° C. for48 hours the conversion was 70%. The polymer swelled in methanol but wasinsoluble in water.

[0063] Similar preparations were achieved with different ratios of themonomers acrolein: acrylic acid namely, 30:70 (Example 9), 10:90(Example 10), 2.5:97.5 (Example 11). The products from Examples 10 and11 were soluble in water and retained by dialysis tubing of exclusion2,000 mwt.

Example 12

[0064] In a similar preparation to the above, 42% conversion wasachieved of a polymer which swelled in methanol or water, from 1.8 gacrolein, 3.3 g vinyl pyrrolidone and 0.071 g azobisisobutyronitrile.

Example 13

[0065] 30 mg benzoyl peroxide was added to a solution of 1.02 gpolyethyleneglycol acrylate and 0.5 ml acrolein in 5 ml methanol. Themixture was stirred and heated to reflux for 48 hours and gave 90%conversion; the residual oil (1.2 g) was chromatographed on SephadexLH-20 (18 g) in methanol. The structure of the resulting polymer wasconfirmed by NMR analysis.

Example 14

[0066] Young adult female mice were inoculated intra-peritoneally with2.3×10⁶ Ehrlich ascites tumour cells and one week later, those mice withswollen abdomens were selected for further experimentation: 15 of suchmice were treated twice a day for three days and 15 once a day for thenext three days, with intra-peritoneal injections of the SubjectPolymers in 0.5% aqueous sodium carbonate at a dose rate of 150 mg/kgmouse; a control group of 15 mice having Ehrlich ascites tumour cellswas treated with the sodium carbonate solution, only. All mice in bothgroups were then sacrificed, the peritoneal fluids were collected andthe number of tumour ceils counted: Control Group Treated GroupPeritoneal Peritoneal Mouse Number cells × 10⁹ Mouse Number cells × 10⁹1 2.30 16 0.97 2 3.55 17 0.54 3 2.13 18 0.14 4 0.05 19 0.06 5 2.55 200.11 6 2.27 21 0.07 7 2.93 22 0.27 8 1.93 23 0.93 9 2.34 24 0.36 10 5.5825 1.04 11 2.23 26 0.12 12 1.65 27 0.64 13 4.76 28 0.16 14 2.01 29 0.6715 3.36 30 0.54 x = 2.64 x = 0.44 s = 1.31 s = 0.35

[0067] A test showed the control and treated groups to be different atgreater than 99% confidence level.

Example 15

[0068] The Subject Polymers were suspended/dissolved in the drinkingwater of piglets, at 0.1% w/v for the first 2-3 days and then at 0.05%w/v for the next 7 days; drinking was ad libitum; consumption of SubjectPolymers was approximately 200 mg/kg of piglet/day.

[0069] Three groups of 28-day, newly-weaned piglets (mean weight 5.6 kg)were studied:

[0070] 1. Treated with Subject Polymer, only;

[0071] 2. Treated with prior vaccination protocol, only;

[0072] 3. No treatment at all (control).

[0073] During the 14-day trial, in keeping with usual practice at thefarm, those piglets which were observed during the daily inspection tohave diarrhea, were given an injection of antibiotic. Treatment:Treatment: No Treatment: Subject Polymers Vaccination Only Control No.28-day 15 19 10 piglets in group No. diarrhea days 0.47 1.11 1.8(mean/piglet) No. injections of 0.6 2.53 4.6 antibiotic (mean/piglet)No. piglets 0.53 0.79 0.9 with heavy E. coli in faeces, day 7(mean/piglet) Weight-gain, 33 32 37 14 days (mean %/piglet)

Example 16

[0074] In a typical small-scale experiment, Subject Polymers (35 g) weredissolved with stirring in water (638 g) containing sodium carbonate (19g), and then the solution was immediately neutralized to pH 7.2 with 10%hydrochloric acid; Sucrose (32 g; sweetening agent) which may bediscretionally included, was added with continued stirring and theneither an absorbent polymer of acrylic acid (64 g; CARBOPOL 934, B.F.Goodrich, USA) or an absorbent copolymer of acrylamide-acrylic acid (64g; ALCOSORB AB 3S, Allied Colloids, England) was added. The resultingswollen beads took-up the typically pale-yellow color of the SubjectPolymers in solution. The beads/pellets may be used wet, but weretypically, either partially or wholly dried at temperatures up to 45°C., before use. However, higher temperatures, up to about 90-100° C. maybe used. On the basis of solid substances added, theoretically, thepellets contain approximately 25% w/w of Subject Polymers.

[0075] Two experiments were undertaken to assess the rate of release ofthe Subject Polymers at simulated pHs of the stomach and the duodenum,respectively. First, the above fully-dried beads (200 mg) were gentlystirred in 0.1M hydrochloric acid (100 mL). An aliquot (10 mL) wasperiodically removed and diluted in excess 0.2M aqueous sodiumbicarbonate; measurement of a peak near 265 nm indicated a maximumrelease, in 0.1M hydrochloric acid, of approximately 35% after aboutforty five minutes. Second, by contrast, a comparable experiment in 0.1Maqueous sodium bicarbonate solution revealed 35% release in about twentyminutes, and 90%-100% after three to five hours. These properties of thebeads were unaffected by heating conditions which may be usedcommercially, to reduce microorganisms in feed (90° C./30 minutes).

Example 17

[0076] In one experiment, two groups, each of ten newly-weaned21-day-old pigs from a commercial piggery were given an oral dose of E.coli (50 mL; 10⁹CFU/mL) of haemolytic E. coli, cultured from a fieldcase of post-weaning colibacillosis. On the same day, one group of thepigs was given ad libitum feeding of 19% crude protein feed containingthe wholly-dried beads/pellets sprinkled in the feed at the rate of3.75% w/w of feed. The pellets contained theoretically, approximately25% w/w of the Subject Polymers. Furthermore, a “No Treatment” group wasgiven feed, only. Each pig consumed about 500 g of feed, daily. Swabswere taken of rectal faeces initially and then again, 48 hours afterdosage with the E. coli. Three days after this regime (during which timetwo pigs of the untreated group died with acute secretory diarrhea), allremaining pigs were sacrificed and the E. coli estimatedsemi-quantitatively in sections of the duodenum (after swabbing themucosa and then using a scale of 4 (highest) to 0 (lowest) within theusual microbiologists' dilution-strike technique on culture plates).Post-mortem examination did not reveal any gastric inflammation in anypig.

[0077] Scores for haemolytic E. coli in the rectal faeces of pigs in thetwo groups on the day of inoculation, and 48-hours later, and areillustrated in the following table: Initial 48 hours later No TreatmentTreatment No Treatment Treatment 1 2 1 0 0 0 3 1 1 1 4 2 1 0 4 0 0 1 3 10 2 2 1 0 1 1 1 1 1 4 0 0 0 4 2 0 0 2 2 Total 4 8 28 10

[0078] After 48 hours the number of haemolytic E. coli in the faeces ofthe pigs receiving the Subject Polymers was significantly less than thatin the untreated pigs (χ²=16.24; p=>0.001).

[0079] Furthermore, the distribution of haemolytic E. coli in the upper(25%) and mid (50%) jejunum of the treated and untreated pigs, aftersacrifice, is recorded below: 25% 50% No Treatment Treatment NoTreatment Treatment  1 1 2 1  0 0 1 0  1 1 4 4  3* 0  4* 0  2 0 3 1  1 12 1  1 3 2 3  4 0 4 0  3* 20  4* 0  1 0 2 0 Total 17 6 28  9

[0080] The treated pigs had significantly fewer haemolytic E coli thanthe untreated pigs, at both 25% site (χ*=7.38; p=<0.01) and the 50% site(χ²=16.24; p=<0.001).

[0081] Another experiment was executed identically, except for the factthat 15 newly-weaned pigs were in each group. The initial inoculation ofE. coli in the experimental group was reduced to one-third of previouslydescribed, and the controlled-release pellets theoretically contained20% w/w of the Subject Polymers. Observations of diarrhea days andweight gain were made of the pigs over 21 days. The results showed thetreated group had statistically significant fewer diarrhea days andstatistically significant (46%) greater weight-gain over the controlgroup. Live Weight Gains and Days of Diarrhea Group Control TreatedNumber 15 15 Mean Initial weight (kg), day 1 4.77 4.43 Standard Error0.22 0.19 Relative (%) 100.00 92.00 Mean Final weight (kg), day 21 6.637.31 Standard Error 0.35 0.36 Relative (%) 100.00 110.30 Mean Daily gain(g), 0-21 days 94.18 137.33 Standard Error 10.27 13.16 Relative (%)*100.00 146.00 Days of diarrhea** 32 13

REFERENCES

[0082] Leman, A. D., Straw, B., Glock, R. D., Mengeline, W. L., Penny,R. H. C. and Scholl, E. (1986). “Diseases of Swine”, 6th Edition, IowaState University Press.

[0083] Robinson, J. R. and Lee, V. H. L. (1987). “Controlled DrugDelivery”. Marcell Dekker.

1. A method of treatment or prevention of a gastrointestinal dysfunctionin a human, animal or bird comprising administering to said human,animal or bird a polymer or copolymer comprising the repeating unitselected from the group consisting of units of formula 1

wherein R is H or C₁ to C₄, and units derived from the unit of formula 1selected from the group consisting of the hydrated, hemiacetal andacetal forms thereof.
 2. The method according to claim 1 wherein thepolymer or copolymer comprises carboxyl groups at a concentration offrom 0.1 to 5 moles of carboxyl groups per kilogram of polymer.
 3. Amethod according to claim 1 wherein said hydrated, hemiacetal and acetalforms are selected from the group consisting of the hydrated diol form,the hemiacetal or acetal form as formed from the condensation of thediol form with the aldehyde or diol form, the tetrahydropyran or fusedtetrohydropyran formed from the condensation of the diol form, thealdol-Michael self-condensation form and mixtures thereof.
 4. The methodaccording to claim 1 wherein said polymer or copolymer is a polymerprepared by ionic initiation and said carboxyl groups are introduced tothe polymer by oxidation with air.
 5. The method according to claim 1wherein said polymer or copolymer has a molecular weight of at least1000.
 6. The method according to claim 1 wherein the gastrointestinaldysfunction is a gastrointestinal disease, gastrointestinal infection ordiarrhoea resulting from an infection of the gastrointestinal tract. 7.The method according to claim 6 wherein the gastrointestinal dysfunctionis a bacterial disease or infection.
 8. The method according to claim 7wherein the bacterial disease or infection is caused by E. coli.
 9. Themethod according to claim 7 wherein the bacterial disease or infectionis cause by H. pylori.
 10. The method according to claim 6 wherein thegastrointestinal disease is cancer.
 11. The method according to claim 1wherein the polymer is administered in the form of a feed.
 12. Themethod according to claim 1 wherein the polymer is administered indrinking water.
 13. The method according to claim 1 wherein the polymeris administered in a form that comprises a controlled release system.14. The method according to claim 13 wherein the controlled releasesystem releases the polymer or copolymer in an alkaline environment. 15.The method according to claim 1 wherein said polymer or copolymer isadministered in an amount up to 5000 mg/kg/day.
 16. The method accordingto claim 1 wherein said polymer or copolymer is administered in anamount from 50 mg/kg/day to 5000 mg/kg/day.
 17. A composition fortreatment of gastrointestinal disease wherein said compositioncomprises: (a) chemotherapeutic active comprising a polymer and/orcopolymer of acrolein, having the repeating polymeric unit:

 wherein R is H or alkyl, preferably C₁ to C₄, or this unit in hydrated,hemiacetal or acetal form; and (b) a pharmaceutical or veterinarallyacceptable carrier.
 18. A chemotherapeutic composition according toclaim 17 in the form of pellets comprising a controlled release systemof a crosslinked water absorbent polymer matrix adapted to form a gelwhen wet.
 19. A chemotherapeutic composition according to claim 17and/or claim 18 wherein the carrier is selected from the groupconsisting of polymers and copolymers of one or more of acrylic acid,methacrylic acid, esters of acrylic acid, esters of methacrylic acid,amides of acrylic acid and amides of methacrylic acid, polyvinyl alcoholand polyvinyl acetate.
 20. A chemotherapeutic composition according toclaim 18 wherein the carrier comprises a polymer of acrylic acid and/ora copolymer of acrylic acid and acrylamide.
 21. A chemotherapeuticcomposition according to claim 17 wherein the active agent is present inan amount of from 5 to 50% by weight of the composition.
 22. Achemotherapeutic composition according to claim 17 comprising a liquidcarrier selected from the group consisting of water, olive oil, peanutoil, sesame oil, sunflower oil, arachis oil, coconut oil, liquidparaffin, ethylene glycol, propylene glycol, polyethylene glycol,polypropylene glycol, ethanol, propanol, isopropanol, glycerol, fattyalcohols, triglycerides and mixtures thereof.
 23. A chemotherapeuticcomposition according to claim 20 wherein the liquid carrier is selectedfrom the group consisting of ethylene glycol, propylene glycol,polyethylene glycol, polypropylene glycol, ethanol propanols,isopropanols, glycerol, fatty alcohols, triglycerides and mixturesthereof.
 24. A chemotherapeutic composition according to claim 23wherein the carrier comprises polyethylene glycol and water.
 25. Achemotherapeutic composition according to claim 17 wherein the carriercomprises controlled release pellets wherein said pellets are added toanimal feed to provide a feed containing from 1% to 20% by weight ofsaid polymer or copolymer of acrolein.
 26. A chemotherapeuticcomposition according to claim 17 wherein the molecular weight of saidpolymer or copolymer of acrolein is greater than
 1000. 27. Achemotherapeutic composition according claim 17 wherein the polymer orcopolymer of acrolein comprises in the range from 0.1 to 5 moles ofcarboxyl groups per kilogram of said polymer or copolymer of acrolein.28. A chemotherapeutic composition according to claim 17 wherein therepeating polymeric unit is in the hydrated diol form, the hemiacetal oracetal form, as formed from the condensation of diol form with thealdehyde or diol form, the tetrahydropyran or fused tetrahydropyranformed from condensation of the diol form, the aldol-Michaelself-condensation form or mixtures thereof illustrated,non-comprehensively by the following formulae:

wherein n is one or more.
 29. A chemotherapeutic composition in the formof pellets comprising: (a) an active agent comprising polymers and/orcopolymers of acrolein having the repeating polymeric unit:

 wherein R is H or alkyl, preferably C₁ to C₄, or this unit is hydrated,hemiacetal or acetal form, together with a pharmaceutically orveterinarally acceptable carrier, and (b) a polymeric matrix withinwhich the active agent is contained;  and wherein the pellets are formedby a process comprising the step of adding a polymeric matrix to asolution and/or suspension and/or emulsion of said polymers and/orcopolymers.
 30. A chemotherapeutic composition according to claim 29,wherein adding said polymeric matrix to a solution and/or suspensionand/or emulsion of the said polymers and/or copolymers, comprises thesteps of: (i) dissolving said polymers or copolymers in an aqueousalkaline or basic solution; (ii) neutralising said solution with acid;(iii) adding to said neutralised solution insoluble, crosslinked,absorbent polymers of acrylic acid and/or copolymers of acrylamide andacrylic acid to form wet swollen pellets.
 31. A chemotherapeuticcomposition according to claim 29 wherein the wet, swollen pellets areat least partly dried.